Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea, hypoxemia, pneumonitis, and pulmonary edema. Longer term consequences of chlorine inhalation include both pulmonary function impairment and structural changes that have been observed in some exposed individuals. Our collaborator Dr. Erik Svendsen has documented pulmonary function abnormalities in a population of individuals who were exposed to chlorine as a result of a large accidental release that occurred in Graniteville, SC in 2005. The results point to a spectrum of respiratory disease states, but suggest that an important component involves small airway disease. An impediment to developing countermeasures for persistent chlorine-induced lung disease is the lack of a relevant animal model for efficacy testing. Our preliminary data indicate that rabbits exposed to chlorine and examined 7 days later exhibit inflammation of the small airways and develop sporadic obliterative lesions characteristic of bronchiolitis obliterans (BO). These animals exhibited normal baseline lung resistance but exhibited hyperreactivity to inhaled methacholine. Based on these preliminary data, we propose to expand on these studies to develop a model in which the obliterative changes to small airways are more widespread resulting in increased baseline lung resistance as has been observed in humans exposed to chlorine gas. We will then assess the efficacy of a potential countermeasure when administered following chlorine exposure for the prevention of small airway disease. The hypotheses to be tested are: 1) Increasing post-exposure monitoring time and/or chlorine dose will produce widespread small airway BO lesions that result in significant increases in baseline lung resistance; and 2) Treatment with inhaled corticosteroid plus - adrenergic agonist after chlorine exposure will inhibit the development of BO lesions and abnormal lung function. Specific Aim 1 will be to develop an animal model of persistent chlorine-induced lung disease that replicates the disease states observed in chlorine-exposed humans. Specific Aim 2 will be to evaluate a currently available therapy (inhaled corticosteroid plus long-acting -adrenergic agonist) in a rabbit model of persistent chlorine-induced lung disease. These exploratory studies will generate valuable information toward development of an appropriate animal model for countermeasure testing and will generate initial data regarding efficacy of a type of treatment currently used for irritant-induced asthma that could be readily adopted as a countermeasure.